Myeloid derived suppressor cells (MDSCs) are increased in numerous pathologic conditions, including infections, inflammatory diseases, graft-versus host disease (GVHD), traumatic stress, and tumor growth. Previous studies have shown that MDSCs can suppress the onset of autoimmune (type 1) diabetes and prevent GVHDs. MDSC-mediated T cell inactivation in vitro has also been reported (Bronte et al., J. Immunol. 2003, 170:270-278; Rodriguez et al., J Immunol. 2003, 171:1232-1239; Bronte et al., Trends Immunol. 2003, 24:302-306; Kusmartsev et al., J. Immunol. 2004, 172: 989-999; Schmielau and Finn, Cancer Res. 2001, 61:4756-4760; Almand et al., J. Immunol. 2001, 166:678; Kusmartsev et al., J. Immunol. 2000, 165:779; Bronte et al., J. Immunol. 1999, 162:5728) MDSCs suppress T-cell responses through production of nitric oxide (NO) (by inducible nitric oxide synthase pathway (iNOS)), arginase, and reactive oxygen species (ROS), and can play an important role in the induction of CD4+CD25+FoxP3+ T regulatory cells through secreting TGF-β and IL-10. [Reviewed in Pan, P. et al. Adv Drug Deliv Rev. 2008 Jan. 14; 60(2): 91-105]. MDSCs exhibit strong immune suppression of T-cell proliferation as well as the ability to induce the development of T regulatory (Treg) cells in tumor-bearing mice. (Pan, P. et al. (2008); Kusmartsev et al. 2000, J. Immunol. 165: 779-785; Huang, et al. 2006, Cancer Res. 66: 1123-1131), however, presently, methods for using MDSCs to induce immune tolerance and to successfully treat inflammatory disease, such as autoimmunity and alloimmune responses are needed.
Alloimmune responses can determine the success or failure of three major transplant events—engraftment of transplanted organs, GVHD and graft-versus-malignancy (GVM) effect. For tissue engraftment, e.g., organ transplantation, immunosuppression of the host immune system permits the transplant to avoid immune rejection. In the case of bone marrow transplantation, immunosuppression of the recipient is needed to allow the graft to gain a foothold. Recipients that do not achieve early donor T cell engraftment are at risk for graft rejection from residual host immune cells (Childs et al., Blood 1999, 94:3234). The direct (contacting antigen presenting cells) or indirect (cytokine induction) expansion of T cells recognizing recipient antigens (alloantigens) leads to tissue damage and GVHD (Ferrara and Deeg, N. Engl. J. Med. 1991, 324:667). GVM is an expansion of transplanted T cells in the bone marrow, but directed against malignant recipient cells, which is a beneficial effect.
Several immunosuppressive compounds exist to combat transplantation rejection, which include, for example, cyclosporine, steroids and methotrexate. However, side effects are associated with each of these drugs, such as kidney toxicity or more rarely neurological problems associated with cyclosporin; weight gain, irritability, and mood swings associated with steroids; and upset stomach, mouth sores, low white blood counts and liver and bone marrow toxicity associated with methotrexate. Attempts to minimize or eliminate GVHD prior to transplantation or transfusion by removing (e.g., with antibodies or by physical separation) or inactivating (e.g., irradiation) donor T cells were unsuccessful because there was an increased risk of rejection, relapse and infectious complications (Horowitz et al., Blood. 1990, 75:555). MDSCs can also inhibit interleukin-2 (IL-2) utilization by NK cells (Brooks et at., 20 Transplantation. 1994, 58:1096) and NK cell activity (Kusmartsev et at., Int. J. Immunopathol. Pharmacol. 1998, 11: 171; Li, H. et al. (2009) “Cancer-Expanded Myeloid-Derived Suppressor Cells Induce Anergy of NK Cells through Membrane-Bound TGF-β1.” J. Immunol; 182, 240-249].
Like GVHD, autoimmunity is also driven by inflammatory immune response. The immune system normally avoid generating autoimmune responses by its ability to distinguish between the body's own cells (self) and foreign invaders (non-self). However, sometimes the immune system's recognition apparatus becomes misdirected and the body begins to mount an immune response directed against its own cells and organs. These misguided T cells and autoantibodies cause what are referred to as autoimmune diseases, which are a varied group of more than 80 serious, chronic illnesses that affect many human organ systems and tissues. For example, T cells that attack pancreas cells contribute to diabetes, while autoantibodies are common in people with rheumatoid arthritis. In another example, patients with systemic lupus erythematosus have antibodies to many types of their own cells and cell components. The treatment of autoimmune diseases depends on the type of disease, how severe it is and the symptoms. Therefore, the treatment may vary from relieving symptoms to preserving organ function (e.g., insulin injections to regulate blood sugar in diabetics) to targeting disease mechanisms (e.g., immunosuppressive drugs or immunomodulators).
Significant progress in understanding the pathogenesis of a family of autoimmune diseases known as inflammatory bowel disease (IBD) has been made in the past few years. Murine models, which mimic many features of IBD, have shown that IBD results from an imbalance between effector and regulatory T cell. Mucosal inflammation has been suggested to cause an excessive effector function against mucosal antigens, which in combination with the lack of regulatory response to these antigens, leads to the development of autoimmune IBD.
To date there are no methods for treating autoimmune diseases or alloimmune reactions that do not have undesirable side-effect profiles. Therefore, there remains a need for a method to treat or prevent autoimmune disease or alloimmune reactions while preserving a GVM effect, and at the same time does not cause severe side effects. The instant invention fills such a need and provides other related advantages.